PROJECT SUMMARY
Neuropsychiatric disorders (NPD), such as schizophrenia, bipolar disorder, and autism are behaviorally-defined
and etiologically-heterogeneous conditions with a wide range of severity and outcomes. For cancer and other
common diseases, the study of rare genetic disorders has illuminated key pathophysiological mechanisms,
resulting in significant treatment advances. We hypothesize that this strategy can be successfully applied to
NPD. New genomic technologies have led to the discovery of hundreds of rare genetic NPD due to copy number
(CNVs) and single gene nucleotide variants (SNVs) of large effect size. However, detailed neuropsychiatric
profiles have not been established for most of these conditions, due in part to difficulty recruiting adequate cohort
sizes to power statistical analyses. We will capitalize on large NPD clinical populations at Geisinger, the
University of Washington, and Washington University in St. Louis to recruit individuals with rare genetic disorders
for this study. We will also examine the influence of additional contributors throughout the genome to the variable
expressivity of neuropsychiatric symptoms in these disorders. This study will systematically examine these
aspects of rare genetic NPD through the following aims: 1) Employ a highly cost-effective, genetics-first
strategy to achieve baseline characterization of a large cohort with genetic NPD etiologies. Every year,
as part of psychiatric, developmental, and behavioral healthcare, valuable genotype and phenotype data are
generated from individuals with rare genetic NPD. We will harmonize core assessment batteries used in clinical
care to leverage this high-quality data for broad data sharing and analyses on >1,000 probands, accelerating
discovery and greatly reducing the research cost of multidimensional phenotyping. 2) Describe detailed
phenotypic signatures in selected rare genetic NPD, including the impact of family background on
variable expressivity. We will characterize quantitative neuropsychiatric traits for selected rare genetic NPD
(1q21.1, 15q13.3, 16p11.2, and 22q11.2 CNVs and CHD8 mutations). All seven disorders have shown genome-
wide significance for increased risk of neuropsychiatric phenotypes, including psychosis, mood disorders, and
autism. We will assess behavioral, psychiatric, and cognitive traits in 720 probands with these rare genetic NPD
and their first-degree family members to explore the impact of family background on variable expressivity of
neuropsychiatric symptoms. 3) Assess the contributions of common and secondary rare genomic variants
to variable expressivity in rare genetic NPD. Through two sub-aims, we will explore the impact of common
(polygenic risk scores) and rare (`second hits') genomic contributors on risk or resilience for neuropsychiatric
symptoms. Analyzing data collected through Aims 1 and 2, in addition to a broader exploration of genomic and
electronic health record data from 250,000 individuals in Geisinger's MyCode cohort, we will demonstrate how
different genomic background contributors lead to clinical heterogeneity in individuals with rare genetic NPD.
These studies may eventually inform individual-level prognoses for neuropsychiatric outcomes.